EP0006772B1 - Thieno and furopyridone derivatives, process for their preparation and medicinal preparations containing them - Google Patents

Thieno and furopyridone derivatives, process for their preparation and medicinal preparations containing them Download PDF

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EP0006772B1
EP0006772B1 EP79400282A EP79400282A EP0006772B1 EP 0006772 B1 EP0006772 B1 EP 0006772B1 EP 79400282 A EP79400282 A EP 79400282A EP 79400282 A EP79400282 A EP 79400282A EP 0006772 B1 EP0006772 B1 EP 0006772B1
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phenyl
halogen atom
furopyridone
thieno
derivatives
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EP0006772A1 (en
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Jean-Pierre Maffrand
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Sanofi SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a medicament containing as active principle derivatives of thieno and furopyridone.
  • a medicament having in particular activities inhibiting platelet aggregation and anti-inflammatory, characterized in that it contains, as active principle, an effective amount of a derivative of thienopyridone or furopyridone corresponding to the formulas following general: in which X is an oxygen or sulfur atom; R represents a hydrogen or halogen atom or a C 4 to C 4 alkyl group and Ar represents a phenyl, naphthyl or pyridyl group, optionally substituted by at least one halogen atom or a lower alkyl or lower alkoxy group , hydroxy, trifluoromethyl or nitro.
  • the subject of the invention is also a process for preparing the derivatives of formula I or II, characterized in that treatment is carried out by heating in an inert solvent and at a temperature between 150 ° C. and the boiling point of the chosen solvent , a compound of formula III or IV below: in which X, R and Ar are as defined above.
  • the solvent inert towards the reactants and reaction products is for example diphenylmethane or diphenyl ether.
  • This reaction by heat treatment involves the transposition of the azides of formula III or IV into isocyanates of formula V or VI which are thermally cyclized into derivatives I and II, according to the reaction scheme below:
  • the starting compounds of formulas III and IV are prepared from the acids of corresponding formulas VII and VIII which are first transformed into acid chlorides of formulas IX and X or mixed anhydrides of formulas XI and XII, the latter being in turn converted in the conventional way to azides, for example by reaction with sodium azide in aqueous solution, according to the reaction scheme below:
  • step a) The filtrate obtained in step a) is added dropwise to 200 cm 3 of diphenylmethane previously heated to 160 ° C, the chloroform being distilled as it goes.
  • the mixture is stirred for another 15 minutes at the same temperature, the mixture is cooled, diisopropyl ether is added, it is filtered, washed with the same ether and dried under vacuum.
  • the compounds of the invention benefit from excellent tolerance and toxicity.
  • the LD 50/24 h / kg of animal body weight, determined in mice according to the Miller and Tainter method for the oral route is greater than 400 mg for all the derivatives.
  • a blood sample is taken from the jugular vein. From this citrated blood and after centrifugation, a plasma containing 600,000 ⁇ 20,000 platelets per mm 3 is reconstituted, which will be used in all aggregation measurements.
  • 0.4 ml of plasma is placed in a silicone tube provided with a magnetic bar itself.
  • the tube is introduced into an aggregometer coupled to a device making it possible to record the variations in optical density.
  • 0.5 ml of a solution containing 10 ⁇ M of A.D.P. is introduced into the tube. (Adenosine-Di Phosphate).
  • the aggregation of platelets then causes an increase in light transmission followed by a decrease consecutive to the disaggregation phase.
  • the maximum variation in optical density thus determined characterized the intensity of the aggregation.
  • A.D.P.'s solution is replaced by a collagen solution (bovine tendon extract).
  • a 1% solution of carrageenan (0.1 ml) is injected into the metatarsal flexors of the right hind paw of the rat at time O.
  • the animals in the treated batch also receive, orally, 100 mg per kg of the derivative to be tested respectively 1 hour before, at the same time as the injection of the phlogogenic agent, then 1 hour and 2 and a half hours after.
  • the measurements which are carried out using the ROCH micrometer at times 0, 1 hour, 2 hours, 3 hours and 5 hours after the administration of the carrageenan make it possible to determine, as a function of time, the percentage of anti activity -inflammatory by comparison with the control group.
  • a simultaneous intraperitoneal injection of 1 ml of ovalbumin and 0.5 ml of a 1% Evans blue aqueous solution is carried out on the rat.
  • the animals in the treated batch are administered per os 100 mg / kg of the derivative to be tested 1 hour before and at the same time as ovalbumin.
  • the intensity of the phenomenon thus provoked is noted by a number ranging from 1 to 5 depending on the progression of the inflammatory syndrome.
  • the average oedematous intensity and the percentage decrease in the oedematous reaction compared to the control are thus determined, as a function of time.
  • the medicament of the invention can be presented for oral administration, in the form of tablets, coated tablets, capsules, drops and syrup. It can also be presented, for rectal administration, in the form of suppositories and for parenteral administration, in the form of an injectable solution.
  • Each unit dose advantageously contains from 0.040 g to 0.750 g of active principle, the doses administered daily being able to vary from 0.040 g to 1.50 g of active principle depending on the age of the patient and the condition treated.
  • the medicament of the invention can thus be administered to humans with profit, as a preventive or curative, in the treatment of diseases causing a pathological modification of the platelet aggregation, such as thromboembolic diseases.

Description

La présente invention est relative à un médicament contenant à titre de principe actif des dérivés de la thiéno et de la furopyridone.The present invention relates to a medicament containing as active principle derivatives of thieno and furopyridone.

Elle ainsi pour objet un médicament ayant notamment des activités inhibitrices de l'agrégation plaquettaire et anti-inflammatoire, caractérisé en ce qu'il contient, à titre de principe actif, une quantité efficace d'un dérivé de thiénopyridone ou de furopyridone répondant aux formules générales suivantes:

Figure imgb0001
dans lesquelles X est un atome d'oxygène ou de soufre; R représente un atome d'hydrogène ou d'halogène ou un groupe alcoyle en C, à C4 et Ar représente un groupe phényle, naphtyle ou pyridyle, éventuellement substitué par au moins un atome d'halogène ou un groupe alcoyle inférieur, alcoxy inférieur, hydroxy, trifluorométhyle ou nitro.It thus relates to a medicament having in particular activities inhibiting platelet aggregation and anti-inflammatory, characterized in that it contains, as active principle, an effective amount of a derivative of thienopyridone or furopyridone corresponding to the formulas following general:
Figure imgb0001
 in which X is an oxygen or sulfur atom; R represents a hydrogen or halogen atom or a C 4 to C 4 alkyl group and Ar represents a phenyl, naphthyl or pyridyl group, optionally substituted by at least one halogen atom or a lower alkyl or lower alkoxy group , hydroxy, trifluoromethyl or nitro.

De tous les composés de formule générale I ou II seul le composé de formule Il dans laquelle R = H, X = S et Ar = C6H5, n'est pas nouveau. Il a déjà été signalé dans la littérature (D.E. AMES et O. RIBEIRO, J.C.S. Perkin I, 1975, 1390), mais il n'a fait l'objet d'aucune étude thérapeutique et son procédé d'obtention est relativement complexe.Of all the compounds of general formula I or II only the compound of formula II in which R = H, X = S and Ar = C 6 H 5 , is not new. It has already been reported in the literature (DE AMES and O. RIBEIRO, JCS Perkin I, 1975, 1390), but it has not been the subject of any therapeutic study and its production process is relatively complex.

L'invention a donc encore pour objet des dérivés de la thiéno ou de la furopyridone répondant aux formules générales suivantes:

Figure imgb0002
dans lesquelles X est un atome d'oxygène ou de soufre, R représente un atome d'hydrogène ou d'halogène ou un groupe alcoyle en C1 à C4 et Ar représente un groupe phényle, naphtyle ou pyridile, éventuellement substitué par au moins un atome d'halogène ou un groupe alcoyle inférieur, alcoxy inférieur, hydroxy, trifluorométhyle ou nitro, sous réserve que l'on n'ait pas simultanément R = H, X = S et Ar= phényle.A subject of the invention is therefore also derivatives of thieno or furopyridone corresponding to the following general formulas:
Figure imgb0002
 in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C 1 to C 4 alkyl group and Ar represents a phenyl, naphthyl or pyridile group, optionally substituted with at least a halogen atom or a lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group, provided that R = H, X = S and Ar = phenyl are not simultaneously present.

L'invention a également pour objet un procédé de préparation des dérivés de formule I ou II, caractérisé en ce qu'on traite par chauffage dans un solvant inerte et à une température comprise entre 150 °C et le point d'ébullition du solvant choisi, un composé de formule III ou IV suivante:

Figure imgb0003
dans lesquelles X, R et Ar sont tels que définis ci-dessus.The subject of the invention is also a process for preparing the derivatives of formula I or II, characterized in that treatment is carried out by heating in an inert solvent and at a temperature between 150 ° C. and the boiling point of the chosen solvent , a compound of formula III or IV below:
Figure imgb0003
 in which X, R and Ar are as defined above.

Le solvant inerte vis-à-vis des réactifs et des produits réactionnels est par exemple le diphénylméthane ou l'éther diphénylique. Cette réaction par traitement thermique fait intervenir la transposition des azides de formule III ou IV en isocyanates de formule V ou VI qui sont cyclisés thermiquement en dérives I et II, suivant le schéma réactionnel ci-dessous:

Figure imgb0004
Figure imgb0005
 The solvent inert towards the reactants and reaction products is for example diphenylmethane or diphenyl ether. This reaction by heat treatment involves the transposition of the azides of formula III or IV into isocyanates of formula V or VI which are thermally cyclized into derivatives I and II, according to the reaction scheme below:
Figure imgb0004
Figure imgb0005

Les composés de départ de formules III et IV sont préparés à partir des acides de formules VII et VIII correspondants qui sont tout d'abord transformés en chlorures d'acides de formules IX et X ou anhydrides mixtes de formules XI et XII, ces derniers étant à leur tour transformés de façon classique en azides, par exemple par réaction avec l'azide de sodium en solution aqueuse, suivant le schéma réactionnel ci-après:

Figure imgb0006
Figure imgb0007
 The starting compounds of formulas III and IV are prepared from the acids of corresponding formulas VII and VIII which are first transformed into acid chlorides of formulas IX and X or mixed anhydrides of formulas XI and XII, the latter being in turn converted in the conventional way to azides, for example by reaction with sodium azide in aqueous solution, according to the reaction scheme below:
Figure imgb0006
Figure imgb0007

Les acides de formule VII suivants, dans lesquels: X = S, R = H, Ar = C6H5; X = S, R = H, Ar = 4-Cl-C6H4; X = S, R = H, Ar = 4-CH3-C6H4; X = S, R = H, Ar = 4-NO2-C6H4 et X = 0, R = H, Ar = C6H5, sont décrits dans la littérature: S. FISICHELLA, G. SCARLATA et D. SCIOTTO, Ann.Chim. (Italia), 1973, 63, 55; S. FISICHELLA, G. MINERI, G. SCARLATA et D. SCIOTTO, ibid. 1973, 63, 779.The following acids of formula VII, in which: X = S, R = H, Ar = C 6 H 5 ; X = S, R = H, Ar = 4-Cl-C 6 H 4 ; X = S, R = H, Ar = 4-CH 3 -C 6 H 4 ; X = S, R = H, Ar = 4-NO 2 -C 6 H 4 and X = 0, R = H, Ar = C 6 H 5 , are described in the literature: S. FISICHELLA, G. SCARLATA and D SCIOTTO, Ann.Chim. (Italia), 1973, 63, 55; S. FISICHELLA, G. MINERI, G. SCARLATA and D. SCIOTTO, ibid. 1973, 63, 779.

Les autres acides de formules (VII) et (VIII) qui sont utilisés dans le procédé de l'invention sont nouveaux et ils ont été préparés par le procédé décrit dans les articles mentionnés ci-dessus, selonle schéma réactionnel suivant:

Figure imgb0008
Figure imgb0009
Les exemples non limitatifs suivants sont donnés à titre d'illustration du procédé de préparation des dérivés de l'invention:The other acids of formulas (VII) and (VIII) which are used in the process of the invention are new and they have been prepared by the process described in the articles mentioned above, according to the following reaction scheme:
Figure imgb0008
Figure imgb0009
 The following nonlimiting examples are given by way of illustration of the process for preparing the derivatives of the invention:

Exemple 1Example 1 Phényl-6-thiéno(3,2-c)pyridone-4 (dérivé 1)Phenyl-6-thieno (3,2-c) pyridone-4 (derivative 1) a) Préparation de l'azide de formule IIIa) Preparation of the azide of formula III

Une solution refroidie à -5 °C de 50 g (0,217 mole) d'acide α-phényl β-(thiényl-2)acrylique dans 31 cm3 (0,22 mole) de triéthylamine et 350 cm3 de chloroforme, on ajoute, goutte à goutte 21 cm3 (~ 0,22 mole) de chloroformiate d'éthyle. Après agitation pendant une demi-heure à -5 °C on introduit, goutte à goutte, une solution de 17 g (0,26 mole) d'azide de sodium dans 60 cm3 d'eau. L'introduction terminée, on agite à 0 °C pendant une heure, on ajoute de l'eau et on décante. La phase organique est lavée à l'eau puis séchée sur sulfate de sodium et filtrée.A solution cooled to -5 ° C of 50 g (0.217 mole) of α-phenyl β- (2-thienyl) acrylic acid in 31 cm 3 (0.22 mole) of triethylamine and 350 cm 3 of chloroform, is added , drop by drop 21 cm 3 (~ 0.22 mole) of ethyl chloroformate. After stirring for half an hour at -5 ° C., a solution of 17 g (0.26 mol) of sodium azide in 60 cm 3 of water is introduced dropwise. When the introduction is complete, the mixture is stirred at 0 ° C. for one hour, water is added and the mixture is decanted. The organic phase is washed with water and then dried over sodium sulfate and filtered.

bJ Préparation du dérivé de formule 1bJ Preparation of the derivative of formula 1

Le filtrat obtenu à l'etape a) est ajouté, goutte à goutte, à 200 cm3 de diphénylméthane préalablement chauffé à 160 °C, le chloroforme étant distillé au fur et à mesure. L'introduction terminée, on agite encore 15 minutes à la même température, on refroidit, on ajoute de l'éther diisopropylique, on filtre, on lave avec le même éther et on sèche sous vide.The filtrate obtained in step a) is added dropwise to 200 cm 3 of diphenylmethane previously heated to 160 ° C, the chloroform being distilled as it goes. When the introduction is complete, the mixture is stirred for another 15 minutes at the same temperature, the mixture is cooled, diisopropyl ether is added, it is filtered, washed with the same ether and dried under vacuum.

On obtient 31.55 g (Rdt: 63,5%) de cristaux beiges: F = 230 °C que l'on-peut recristalliser dans un mélange méthanol-diméthylformamide.31.55 g are obtained (yield: 63.5%) of beige crystals: M = 230 ° C. which can be recrystallized from a methanol-dimethylformamide mixture.

Exemple 2Example 2 p-fluorophényl-6 thiéno(3,2-c)pyridone-4, (dérivé 2)p-fluorophenyl-6 thieno (3,2-c) pyridone-4, (derivative 2)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(fluoro-4 phényl β-(thiényl-2)acrylique (F== 191 °C): Cristaux beiges, F = 262 °C (méthanol-diméthylformamide) rendement: 44,5%.Prepared according to the procedure of Example 1 from α- (4-fluoro-phenyl β- (2-thienyl) acrylic acid (F == 191 ° C): Beige crystals, F = 262 ° C (methanol -dimethylformamide) yield: 44.5%.

Exemple 3Example 3 o-chlorophényl-6 thiéno(3,2-c)pyridone-4, (dérivé 3)o-chlorophenyl-6 thieno (3,2-c) pyridone-4, (derivative 3)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(chloro-2 phényl) β-(thiényl-2)acrylique (F = 197 °C): Cristaux beiges, F = 232 °C, rendement: 27%.Prepared according to the procedure of Example 1 from α- (2-chloro-phenyl) β- (2-thienyl) acrylic acid (M = 197 ° C): Beige crystals, M = 232 ° C, yield : 27%.

Exemple 4Example 4 p-chlorophényl-6 thiéno(3,2,-c)pyridone-4, (dérivé 4)p-chlorophenyl-6 thieno (3,2, -c) pyridone-4, (derivative 4)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α (chloro-4 phényl) β-(thiényl-2)acrylique (F = 224 °C): Cristaux vert pâle, F > 260 °C, rendement: 60%.Prepared according to the procedure of Example 1 from α (4-chloro-phenyl) β- (2-thienyl) acrylic acid (F = 224 ° C): Pale green crystals, F> 260 ° C, yield : 60%.

Exemple 5Example 5 p-tolyl-6 thiéno(3,2-c)pyridone-4, (dérivé 5) p - tolyl- 6 thieno (3,2-c) pyridone - 4, ( derivative 5)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(p-tolyl) β-(thiényl-2) acrylique (F = 209 °C): Cristaux jaunes, F > 260 °C (méthanol-diméthylformamide), Rdt: 51%.Prepared according to the procedure of Example 1 from α- (p-tolyl) β- (2-thienyl) acrylic acid (F = 209 ° C): Yellow crystals, F> 260 ° C (methanol- dimethylformamide), YId: 51%.

Exemple 6Example 6 p-methoxyphényl-6 thiéno(3,2-c)pyridone-4, (dérive 6)p-methoxyphenyl-6 thieno (3,2-c) pyridone-4, (derivative 6)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(méthoxy-4 phényl) β-(thiényl-2)acrylique (F = 203 °C): Cristaux verdâtres, F = 251 °C (diméthylformamide), rendement: 64%.Prepared according to the procedure of Example 1 from α- (4-methoxyphenyl) β- (2-thienyl) acrylic acid (F = 203 ° C): Greenish crystals, F = 251 ° C (dimethylformamide ), yield: 64%.

Exemple 7Example 7 (diméthoxy-3,4 phényl)-6 thiéno (3,2-c)pyridone-4, (dérivé 7)(3,4-dimethoxy phenyl) -6 thieno (3,2-c) pyridone-4, (derivative 7)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide a-(diméthoxy-3,4 phényl) β-(thiényl-2)acrylique (F =220 °C): Cristaux jaunes, F=220 °C (méthanol-diméthylformamide, Rdt: 60,5 %)Prepared according to the procedure of Example 1 starting from a- (3,4-dimethoxyphenyl) β- (2-thienyl) acrylic acid (F = 220 ° C): Yellow crystals, F = 220 ° C (methanol-dimethylformamide, Yield: 60.5%)

Exemple 8Example 8 (triméthoxy,3,4,5 phényl)-6 thiéno(3,2-c)pyridone-4, (dérivé 8)(trimethoxy, 3,4,5 phenyl) -6 thieno (3,2-c) pyridone-4, (derivative 8)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(triméthoxy-3,4,5 phényl) β-(thiényl-2)acrylique (F = 217 °C): Cristaux jaunes, F = 240 °C (méthanol-diméthylformamide), Rdt: 62 %.Prepared according to the procedure of Example 1 from α- (3,4,5-phenylphenyl) β- (2-thienyl) acrylic acid (M = 217 ° C): Yellow crystals, M = 240 ° C (methanol-dimethylformamide), Yield: 62%.

Exemple 9Example 9 o-nitrophényl-6 thiéno(3,2-c)pyridone-4, (dérivé 9)o-nitrophenyl-6 thieno (3,2-c) pyridone-4, (derivative 9)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(nitro-2 phényl) β-(thiényl-2)acrylique (F = 211 °C): Cristaux jaunes, F = 236 °C (méthanol-diméthylformamide), Rdt: 20 %.Prepared according to the procedure of Example 1 from α- (2-nitro-phenyl) β- (2-thienyl) acrylic acid (F = 211 ° C): Yellow crystals, F = 236 ° C (methanol -dimethylformamide), Yield: 20%.

Exemple 10Example 10 p-nitrophényl-6 thiéno(3,2-c)pyridone-4, (dérivé 10)p-nitrophenyl-6 thieno (3,2-c) pyridone-4, (derivative 10)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(nitro-4 phényl) β-(thiényl-2)acrylique (F = 236 °C): Cristaux jaunes, F > 260 °C, rendement: 51 %.Prepared according to the procedure of Example 1 from α- (4-nitro-phenyl) β- (2-thienyl) acrylic acid (F = 236 ° C) : Yellow crystals, F> 260 ° C, yield : 51%.

Exemple 11Example 11 m-trifluorométhylphényl-6 thiéno(3,2-c)pyridone-4 (dérivé 11)m-trifluoromethylphenyl-6 thieno (3,2-c) pyridone-4 (derivative 11)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(trifluorométhyl-3 phényl) β-(thiényl-2) acrylique (F = 232 °C) Cristaux blancs, F = 245 °C (méthanol-diméthylformamide), Rdt: 58 %.Prepared according to the procedure of Example 1 from α- (3-trifluoromethyl-phenyl) β- (2-thienyl) acrylic acid (F = 232 ° C) White crystals, F = 245 ° C (methanol- dimethylformamide), Yield: 58%.

Exemple 12Example 12 Chloro-2 phényl-6 thiéno(3,2-c)pyridone-4, (dérivé 12)2-Chloro-6-phenyl thieno (3,2-c) pyridone-4, (derivative 12)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-phényl β-(Chloro-5 thiényl-2)acrylique (F = 215 °C) Cristaux orangés, F > 260 °C (diméthylformamide), Rdt: 64 %.Prepared according to the procedure of Example 1 from α-phenyl β- (5-chloro-2-thienyl) acrylic acid (F = 215 ° C) Orange crystals, F> 260 ° C (dimethylformamide), Yield : 64%.

Exemple 13Example 13 Méthyl-2 phényl-6 thiéno(3,2-c)pyridone-4, (dérivé 13)2-methyl-6-phenyl thieno (3,2-c) pyridone-4, (derivative 13)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-phényl β-(méthyl-5 thiényl-2)acrylique (F = 207 °C) Cristaux beiges, F > 260 °C (diméthylformamide), Rdt: 54 %.Prepared according to the procedure of Example 1 from α-phenyl β- (5-methyl-2-thienyl) acrylic acid (F = 207 ° C) Beige crystals, F> 260 ° C (dimethylformamide), Yd : 54%.

Exemple 14Example 14 (Pyridyl-3)-6 thiéno(3,2-c)pyridone-4, (dérivé 14)(Pyridyl-3) -6 thieno (3,2-c) pyridone-4, (derivative 14)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(pyridyl-3) β-(thiényl-2)acrylique (F = 210 °C) Cristaux jaunes, F > 260 °C (diméthylformamide), rendement: 41 %.Prepared according to the procedure of Example 1 from α- (pyridyl-3) β- (2-thienyl) acrylic acid (F = 210 ° C) Yellow crystals, F> 260 ° C (dimethylformamide), yield: 41%.

Exemple 15Example 15 Phényl-5 thiéno(2,3-c)pyridone-7, (dérivé 15)5-phenyl thieno (2,3-c) pyridone-7, (derivative 15)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-phényl β-(thiényl-3)acrylique (F = 175 °C) Cristaux rosés, F = 203°C méthanol-diméthylformamide), Rdt: 50 %.Prepared according to the procedure of Example 1 from α-phenyl β- (3-thienyl) acrylic acid (F = 175 ° C) Pink crystals, F = 203 ° C methanol-dimethylformamide), Yield: 50 %.

Exemple 16Example 16 o-chlorophényl-5 thiéno(2,3-c)pyridone-7, (dérivé 16)o-chlorophenyl-5 thieno (2,3-c) pyridone-7, (derivative 16)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide a-(chloro-2-phényl) β-(thiényl-3)acrylique (F = 196 °C) Cristaux beiges, F = 229 °C, rendement: 39 %.Prepared according to the procedure of Example 1 from a- (chloro-2-phenyl) β- (thienyl-3) acrylic acid (M = 196 ° C) Beige crystals, M = 229 ° C, yield : 39%.

Exemple 17Example 17 Phényl-6 furo(3,2-c)pyridone-4, (dérivé 17)6-phenyl furo (3,2-c) pyridone-4, (derivative 17)

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-phényl β-(furyl-2)acrylique (F = 146 °C): Cristaux beiges, F = 210 °C, rendement: 65 %.Prepared according to the procedure of Example 1 from α-phenyl β- (furyl-2) acrylic acid (M = 146 ° C): Beige crystals, M = 210 ° C, yield: 65%.

Exemple 18Example 18 α-naphtyl-6 furo(3,2-c)pyridone-4α-naphthyl-6 furo (3,2-c) pyridone-4

Préparée selon le mode opératoire de l'exemple 1 à partir de l'acide α-(naphtyl-1) β-(furyl-2)acrylique (F = 219 °C). Cristaux beiges, F = 230 °C, rendement: 39,5 %.Prepared according to the procedure of Example 1 from α- (naphthyl-1) β- (furyl-2) acrylic acid (M = 219 ° C). Beige crystals, M = 230 ° C, yield: 39.5%.

Les résultats des essais toxicologiques et pharmacologiques qui sont rapportés ci-après, mettent en évidence les intéressantes activités des dérivés de l'invention, notamment inhibitrice de l'agrégation plaquettaire et anti-inflammatoire.The results of the toxicological and pharmacological tests which are reported below, put highlight the interesting activities of the derivatives of the invention, in particular inhibitor of platelet aggregation and anti-inflammatory.

1 - Etude Toxicologique1 - Toxicological study

Les composés de l'invention bénéficient d'une excellente tolérance et d'une toxicité. Ainsi, la DL50/24 h/kg de poids corporel d'animal, déterminée chez la souris selon la méthode de Miller et Tainter pour-la voie orale, est supérieure à 400 mg pour tous les dérivés.The compounds of the invention benefit from excellent tolerance and toxicity. Thus, the LD 50/24 h / kg of animal body weight, determined in mice according to the Miller and Tainter method for the oral route, is greater than 400 mg for all the derivatives.

En outre, les essais effectués sur la toxicité aigüe, chronique sub-chronique et retardée, chez diverses espèces animales, n'ont mis en évidence aucune réaction locale ou générale, aucune perturbation dans les contrôles biologiques régulièrement effectués, aucune anomalie dans les examens microscopiques et macroscopiques chez les animaux sacrifiés et autopsiés en fin d'expérimentation.In addition, the tests carried out on acute, chronic sub-chronic and delayed toxicity, in various animal species, did not show any local or general reaction, no disturbance in the biological controls regularly carried out, no anomaly in microscopic examinations. and macroscopic in animals sacrificed and autopsied at the end of the experiment.

Il - Etude PharmacologiqueIt - Pharmacological Study 1°― Action inhibitrice de l'agrégation plaquettaire1 ° - Inhibitory action on platelet aggregation

Chez des rats de souche Wistar, on effectue un prélèvement sanguin dans la veine jugulaire. A partir de ce sang citraté et après centrifugation, on reconstitue un plasma contenant 600 000 ± 20 000 plaquettes par mm3, qui servira dans toutes les mesures d'agrégation.In rats of Wistar strain, a blood sample is taken from the jugular vein. From this citrated blood and after centrifugation, a plasma containing 600,000 ± 20,000 platelets per mm 3 is reconstituted, which will be used in all aggregation measurements.

a) mesure de l'agrégation plaquettaire à l'A.D.P.a) measurement of platelet aggregation at A.D.P.

On place 0,4 ml de plasma dans un tube siliconé pourvu d'une barre aimantée ellemême siliconée. Le tube est introduit dans un agrégomètre couplé à un appareil permettant d'enregistrer les variations de densité optique. Lorsque la transmission de la lumière a atteint une valeur stable, on introduit dans le tube 0,5 ml d'une solution contenant 10 µM d'A.D.P. (Adénosine-Di Phosphate).0.4 ml of plasma is placed in a silicone tube provided with a magnetic bar itself. The tube is introduced into an aggregometer coupled to a device making it possible to record the variations in optical density. When the light transmission has reached a stable value, 0.5 ml of a solution containing 10 μM of A.D.P. is introduced into the tube. (Adenosine-Di Phosphate).

L'agrégation des plaquettes provoque alors une augmentation de la transmission lumineuse suivie d'une diminution consécutive à la phase de désagrégation.The aggregation of platelets then causes an increase in light transmission followed by a decrease consecutive to the disaggregation phase.

La variation maximale de densité optique ainsi déterminée caractérisé l'intensité de l'agrégation.The maximum variation in optical density thus determined characterized the intensity of the aggregation.

b) mesure de l'agrégation plaquettaire au collagène.b) measurement of collagen platelet aggregation.

La solution d'A.D.P. est remplacée par une solution de collagène (extrait de tendons bovins).A.D.P.'s solution is replaced by a collagen solution (bovine tendon extract).

c) résultats.c) results.

Différents lots de 20 rats sont utilisés, chaque lot recevant un dérivé à tester par la voie orale, à la dose de 100 mg/kg de poids corporel. Les résultats obtenus au cours de ces 2 essais sont rapportés dans le Tableau 1 suivant qui indique le pourcentage d'inhibition de l'agrégation plaquettaire obtenu, par rapport au témoin, 3 heures après le traitement par le médicament de l'invention, dans le test de l'A.D.P. et au collagène.

Figure imgb0010
Different batches of 20 rats are used, each batch receiving a derivative to be tested by the oral route, at a dose of 100 mg / kg of body weight. The results obtained during these 2 tests are reported in the following Table 1 which indicates the percentage of inhibition of platelet aggregation obtained, relative to the control, 3 hours after treatment with the drug of the invention, in the ADP and collagen test.
Figure imgb0010

2° - Action anti-inflammatoire2 ° - Anti-inflammatory action a) méthode de l'oedème localisé provoqué par la carragénine.a) method of localized edema caused by carrageenan.

Une solution de carragénine (0,1 ml) à 1% est injectée dans les fléchisseurs métatarsiens de la patte postérieure droite du rat au temps O. Les animaux du lot traité reçoivent en outre, par la voie orale, 100 mg par kg du dérivé à tester respectivement 1 heure avant, en même temps que l'injection de l'agent phlogogène, puis 1 heure et 2 heures et demi après. Les mesures qui sont effectuées à l'aide du micromètre de ROCH aux temps 0, 1 heure, 2 heures, 3 heures et 5 heures après l'administration de la carragénine permettent de déterminer, en fonction du temps, le pourcentage d'activité anti-inflammatoire par comparaison avec le lot témoin.A 1% solution of carrageenan (0.1 ml) is injected into the metatarsal flexors of the right hind paw of the rat at time O. The animals in the treated batch also receive, orally, 100 mg per kg of the derivative to be tested respectively 1 hour before, at the same time as the injection of the phlogogenic agent, then 1 hour and 2 and a half hours after. The measurements which are carried out using the ROCH micrometer at times 0, 1 hour, 2 hours, 3 hours and 5 hours after the administration of the carrageenan make it possible to determine, as a function of time, the percentage of anti activity -inflammatory by comparison with the control group.

Les résultats sont consignés au tableau Il suivant:

Figure imgb0011
The results are recorded in Table II below:
Figure imgb0011

b) méthode de l'oedème généralisé à l'ovalbumine.b) generalized ovalbumin edema method.

Une injection intrapéritonéale simultanée de 1 ml d'ovalbumine et de 0,5 ml d'une solution aqueuse de bleu Evans à 1 % est effectuée sur le rat. D'autre part, on administre per os aux animaux du lot traité 100 mg/kg du dérivé à tester 1 heure avant et en même temps que l'ovalbumine. L'intensité du phénomène ainsi provoqué est notée par un chiffre allant de 1 à 5 suivant la progression du syndrome inflammatoire. On détermine ainsi la moyenne de l'intensité oedémateuse et le pourcentage de diminution de la réaction oedémateuse par rapport au témoin, en fonction du temps.A simultaneous intraperitoneal injection of 1 ml of ovalbumin and 0.5 ml of a 1% Evans blue aqueous solution is carried out on the rat. On the other hand, the animals in the treated batch are administered per os 100 mg / kg of the derivative to be tested 1 hour before and at the same time as ovalbumin. The intensity of the phenomenon thus provoked is noted by a number ranging from 1 to 5 depending on the progression of the inflammatory syndrome. The average oedematous intensity and the percentage decrease in the oedematous reaction compared to the control are thus determined, as a function of time.

Les pourcentages d'activité anti-inflammatoire obtenus à la 2ème heure et 3eme heure après l'injection d'ovalbumine sont consignés dans le Tableau III suivant.

Figure imgb0012
The percentages of anti-inflammatory activity obtained at the 2nd hour and 3rd hour after the injection of ovalbumin are recorded in the following Table III.
Figure imgb0012

Les résultats de ces études mettent en évidence la bonne tolérance et les intéressantes propriétés inhibitrice de l'agrégation plaquettaire et anti-inflammatoire des dérivés de formules I et II, qui les rendent très utiles en médecine humaine et vétérinaire.The results of these studies demonstrate the good tolerance and the interesting inhibitory properties of platelet aggregation and anti-inflammatory of derivatives of formulas I and II, which make them very useful in human and veterinary medicine.

Le médicament de l'invention peut être présenté pour l'administration orale, sous forme de comprimés, comprimés dragéifiés, capsules, gouttes et sirop. Il peut aussi être présenté, pour l'administration rectale, sous forme de suppositoires et pour l'administration parentérale, sous forme de soluté injectable.The medicament of the invention can be presented for oral administration, in the form of tablets, coated tablets, capsules, drops and syrup. It can also be presented, for rectal administration, in the form of suppositories and for parenteral administration, in the form of an injectable solution.

Chaque dose unitaire contient avantageusement de 0,040 g à 0,750 g de principe actif, les doses administrables journellement pouvant varier de 0,040 g à 1,50 g de principe actif selon l'âge du patient et l'affection traitée.Each unit dose advantageously contains from 0.040 g to 0.750 g of active principle, the doses administered daily being able to vary from 0.040 g to 1.50 g of active principle depending on the age of the patient and the condition treated.

On donnera ci-après, à titre d'exemples non limitatifs quelques formulations pharmaceutiques du médicament de l'invention.

  • 1 °)Comprimes dérivé n° 1 0,125 g excipient: lactose, polyvinylpyrrolidone, acide alginique, fécule de pomme de terre, stéarate de magnésium.
  • 2°)Comprimes Drageifies dérivé n° 4 0,100 g excipient: eudragit S, talc, stéarate de magnésium, gomme arabique, sucre blanc officinal, cire blanche, cire de carnauba.
  • 3°) Capsules dérivé n°6 0,150 g excipient: stéarate de magnésium, talc, lactose
  • 4°) Ampoules Injectables dérivé n° 12 0,100 g excipient: solvant isotonique q.s.p. 3 ml
  • 5°) Suppositoires dérivé n° 15 0,150 g excipient: triglycérides semi synthétiques
Some pharmaceutical formulations of the medicament of the invention will be given below, by way of nonlimiting examples.
  • 1 °) Tablets derivative n ° 1 0.125 g excipient: lactose, polyvinylpyrrolidone, alginic acid, potato starch, magnesium stearate.
  • 2 °) Drageifies tablets derivative n ° 4 0.100 g excipient: eudragit S, talc, magnesium stearate, gum arabic, officinal white sugar, white wax, carnauba wax.
  • 3 °) Derivative capsules n ° 6 0.150 g excipient: magnesium stearate, talc, lactose
  • 4 °) Injectable ampoules derivative n ° 12 0.100 g excipient: isotonic solvent qs 3 ml
  • 5 °) Derivative suppositories n ° 15 0.150 g excipient: semi synthetic triglycerides

Les études toxicologiques et pharmacologiques qui viennent d'être rapportées ont mis en évidencé la faible toxicité des dérivés de l'invention ainsi que leurs remarquables actions inhibitrices de l'agrégation plaquettaire et anti-inflammatoire.The toxicological and pharmacological studies which have just been reported have brought to light the low toxicity of the derivatives of the invention as well as their remarkable actions inhibiting platelet aggregation and anti-inflammatory.

Le médicament de t'invention peut ainsi être administré à l'homme avec profit, à titre préventif ou curatif, dans le traitement des maladies provoquant une modification pathologique de l'agrégation plaquettaire, telle que les maladies thrombo-emboliques.The medicament of the invention can thus be administered to humans with profit, as a preventive or curative, in the treatment of diseases causing a pathological modification of the platelet aggregation, such as thromboembolic diseases.

Il peut aussi être administre pour ses propriétés anti-inflammatoires et anti-oedémateuses dans le traitement de toutes les réactions inflammatoires sans pour cela interférer sur l'évolution du processus pathologique sous-jacent. Il est indiqué dans la poly-arthrite rhumatoïde, l'arthrose, la coxarthrose, la spondylarthrite ankylosante, la goutte, les affections aiguës de l'appareil locomoteur, en chirurgie post-opératoire et en odonto-stomatologie.It can also be administered for its anti-inflammatory and anti-edematous properties in the treatment of all inflammatory reactions without interfering with the development of the underlying pathological process. It is indicated in rheumatoid arthritis, osteoarthritis, hip osteoarthritis, ankylosing spondylitis, gout, acute musculoskeletal conditions, in postoperative surgery and odonto-stomatology.

Claims (6)

1. Therapeutic composition having, in particular blood-platelet aggregation inhibiting and antiinflammatory activities comprising, as active ingredient, an efficient amount of a thienopyridone or furopyridone derivative having the following general formulae:
Figure imgb0021
in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C,4 alkyl group, and Ar represents a phenyl, naphthyl or pyridyl group optionally substituted with at least a halogen atom or a lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group.
2. Therapeutic composition as claimed in claim 1, formulated in a form suitable for oral, parenteral or rectal administration, the active ingredient being combined with a therapeutically acceptable carrier.
3. Therapeutic composition as claimed in any one of the claims 1 and 2, in unit dosage form, each unit dose containing 0.40-0.750 g active ingredient.
4. Thieno- or furopyridone derivatives having the following general formulae:
Figure imgb0022
in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C1-4 alkyl group, and Ar represents a phenyl, naphthyl or pyridyl group optionally substituted with at least a halogen atom or a lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group, provided R = H, X = S and Ar = phenyl are not simultaneously present.
5. Process for the preparation of thienopyridone or furopyridone derivatives having the following general formulae:
Figure imgb0023
in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C1-4 alkyl group, and Ar represents a phenyl, naphthyl or pyridyl group optionally substituted with at least a halogen atom or a lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group, comprising heating within an inert solvent and at a temperature between 150°C and the boiling point of the solvent selected, a compound of the following formulae (III) or (IV):
Figure imgb0024
in which X, R and Ar have the above-defined meanings.
6. Process as claimed in claim 5, wherein the inert solvent is selected from diphenylmethane and diphenyl ether.
EP79400282A 1978-06-22 1979-05-02 Thieno and furopyridone derivatives, process for their preparation and medicinal preparations containing them Expired EP0006772B1 (en)

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